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Date of Award

Summer 2024

Document Type

Masters Thesis

Department or Program Affiliation

Chemistry

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Spiegel, P. Clint

Second Advisor

Anthony-Cahill, Spencer J.

Third Advisor

Smirnov, Sergey L.

Abstract

Abstract

Factor VIII and von Willebrand factor (vWF) are essential for blood coagulation. FVIII, a large glycoprotein with 2332 amino acids, is crucial in the intrinsic pathway of coagulation. After secretion, FVIII circulates in the bloodstream at approximately one nanomolar concentration, bound to vWF, which protects it from rapid clearance. In response to vascular injury, FVIII is proteolytically activated, dissociates from vWF, and binds to activated platelet surfaces and activated Factor IX, dramatically accelerating the rate of blood clot formation. Hemophilia A, affecting 1 in 5000 males, results from functional FVIII deficiency. Standard treatment involves prophylactic FVIII injections but has limitations like frequent dosing and antibody development. Understanding FVIII's role can improve therapy and lead to engineered treatments with extended half-lives and reduced immunogenicity, benefiting hemophilia A patients. vWF binds to and stabilizes FVIII, preventing premature clearance, crucial for hemostasis. Dysregulation can lead to bleeding disorders or thrombotic diseases. Understanding FVIII's interaction with vWF is vital for targeted therapies. Low-density lipoprotein receptor-related protein 1 ( LRP1) regulates clotting protein levels, tames tissue factor activity, potentially influencing platelet adhesion, and keeps blood vessels strong.

This thesis reports the production, characterization, and interaction between LRP1 Complimentary repeats 7-8 & 28-29 and FVIII in vitro. Additionally, it seeks to investigate the impact of antibodies on this interaction. Furthermore, the study aims to produce, crystallize, and characterize the von Willebrand Factor D4 domain in HEK293 cells.

Type

Text

Publisher

Western Washington University

OCLC Number

1456161397

Subject – LCSH

Blood coagulation factor VIII; Blood coagulation factors; Hemophilia--Treatment; Von Willebrand disease--Treatment

Format

application/pdf

Genre/Form

masters theses

Language

English

Rights

Copying of this document in whole or in part is allowable only for scholarly purposes. It is understood, however, that any copying or publication of this document for commercial purposes, or for financial gain, shall not be allowed without the author’s written permission.

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